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SUMMARY Excessive and unresolved neuroinflammation is a key component of the pathological cascade in brain injuries such as ischemic stroke. Here, we report that TRIM9, a brain-specific tripartite motif (TRIM) protein, was highly expressed in the peri-infarct areas shortly after ischemic insults in mice, but expression was decreased in aged mice, which are known to have increased neuroinflammation after stroke. Mechanistically, TRIM9 sequestered β-transducin repeat-containing protein (β-TrCP) from the Skp-Cullin-F-box ubiquitin ligase complex, blocking IκBα degradation and thereby dampening nuclear factor κB (NF-κB)-dependent proinflammatory mediator production and immune cell infiltration to limit neuroinflammation. Consequently, Trim9-deficient mice were highly vulnerable to ischemia, manifesting uncontrolled neuroinflammation and exacerbated neuropathological outcomes. Systemic administration of a recombinant TRIM9 adeno-associated virus that drove brain-wide TRIM9 expression effectively resolved neuroinflammation and alleviated neuronal death, especially in aged mice. These findings reveal that TRIM9 is essential for resolving NF-κB-dependent neuroinflammation to promote recovery and repair after brain injury and may represent an attractive therapeutic target., Graphical Abstract, In Brief Neuroinflammation drives pathology during brain injury. Zeng et al. show that TRIM9 is induced after ischemic insults in young mice, but not old mice, and promotes resolution of neuroinflammation. AAV-mediated TRIM9 therapy in aged mice restricts neuroinflammation and alleviates stroke damage, representing a potential therapeutic target for brain injury.

Author Tony Hiss, who writes about Deep Travel in his insightful book, In Motion: The Experience of Travel , calls experiencing Deep Travel as “a different way of being awake.” He believes moments of Deep Travel can bring us fully into a landscape transformed – to refresh and enrich us as we journey within our mode of transport, to bring us ultimately into a state of awe. Hiss also emphasizes that our instinct for what is beautiful and awe-inspiring dims as we reach adulthood. He stresses the importance of keeping alive our inborn sense of wonder, and focusing on re-connecting, as we travel, with what is familiar and what is remarkable in our “in motion” lives. Recent health research has shown a correlation between heighten moments of travel experience and positive health effects. Gretchen Reynolds, in a recent New York Times article, noted that individuals who have reported feeling awestruck, have lower levels of interleukin-6 which is linked to inflammation. So the more remarkable the travel experience, the more awe we feel, could in fact reduce the risk of heart disease and stroke. Dr. Kelter, a professor of psychology at Berkeley, has noted that the human system is wired to “to feel a sense of reverence and awe for the collective.” In his book, Born to Be Good , he notes “prototypical experiences of awe, involve perceived vastness, anything that is experienced as much larger than the self…” such as a grand travel experience; and it is these heightened experiences that can transport us to a new sense of being. In this presentation, the author first establishes the links between heightened moments of Deep Travel and our sense of well-being and wonder. Second, the author provides health research examples that correlate our heightened state of remarkable travel experiences to life enduring, positive health effects. The more awe in our lives the more we are lifted out of ourselves, to the unfamiliar, the unexplored, the amazing, that bring us wonder. To conclude, the author offers through images, spoken word, and indigenous music moments of Deep Travel experiences – for example, a walk in the Hoh Rain Forest; a summit climb to the top of Mt. Rainier; traveling 180 mph on Eurostar Rail through the Chunnel to Paris – to transport the audience to the place of wonder and bring us all closer to a new life discipline of awe-struck as we travel healthier.

Application of nanometer thick fluoropolymer films onto metal and semiconducting substrates is described. In the first step, nanometer-sized polymer particles are generated by a process of homogeneous nucleation during the rapid expansion of supercritical fluid solutions. These gas-phase particles are then charged as they are being formed by application of a high voltage to the expansion nozzle. In this way the charged nanoparticles can be collected on a solid surface forming uniform coatings with thicknesses from tens of nanometers to several micrometers thick. Supercritical carbon dioxide solutions of three different fluoropolymers were used to generate different types of coatings. This represents a ‘green’ process for film deposition. A further unique aspect of this process is that the small charged nanoparticles can be deposited to electrically conducting microscopic regions with a spatial resolution better than 50 nm.

Recombinant adeno-associated viruses (rAAVs) are commonly used vehicles for in vivo gene transfer. However, the tropism repertoire of naturally occurring AAVs is limited, prompting the development of novel AAV capsids with more desirable transduction characteristics. We have developed a capsid selection method, called Cre-recombination-based AAV targeted evolution (CREATE), that enables the identification of AAV capsids that more efficiently transduce defined cell populations in vivo (Deverman et al. in press, Nature Biotechnology). We generated AAV capsid libraries and used CREATE to identify variants that cross the blood brain barrier and efficiently and widely transduce astrocytes in the mouse central nervous system (CNS) after intravenous injection. One variant, AAVPHP. B, transfers genes throughout the adult CNS with an efficiency that is 40- to 92-fold greater (depending on the CNS region) than that of the current standard, AAV9. It transduces the majority of astrocytes and neurons across multiple CNS regions, and in vitro, it transduces human neurons and astrocytes more efficiently than does AAV9. We are now evolving AAV-PHP.B for even greater transduction of specific CNS cell types as a means to both develop more effective vectors and to gain insight into the mechanism of enhanced transduction. Our identification of AAV-PHP.B and several other enhanced vectors after only two rounds of selection establishes CREATE as a powerful method to customize AAV vectors for biomedical applications.

The discovery two decades ago that the Philadelphia chromosome encodes an oncogenic fusion of Bcr and Abl remains among the most important contributions to our understanding of the process of malignant transformation. We now know that Bcr-Abl is one of more than 30 aberrantly activated tyrosine kinases that are expressed in a variety of tumors. Conventional treatment of the tumors in which these proteins are expressed is usually doomed to failure because the activated tyrosine kinases render the tumor cells stubbornly resistant to apoptosis. In this context, it is notable that Zhao and coworkers have uncovered a novel weapon in the resistance armamentarium of these rogue kinases, the suppression of the inactivating deamidation of Bcl-xL (this issue of Cancer Cell).